Much of our general understanding of coactivator function stems from characterizations of the p160/Steroid Receptor Coactivator (SRC) family of coregulators, which comprises SRC-1, -2, and -3 full length (SRC-3FL). Our prior work revealed that coactivators are controlled by a complex posttranslational modification (PTM) code that triggers a multitude of changes to regulate their molecular functions. Such PTM-induced changes explain how a single SRC coregulates diverse transcriptional outputs that enable the execution of wide-ranging physiological and pathophysiological responses, including even nongenomic activities in the cytoplasm and cell membrane. These non-nuclear roles for coactivators have been significantly expanded through our discovery of a new SRC-3 isoform (SRC-3?4) which functions as an essential molecular adaptor for growth factor induced signaling at the plasma membrane. Because our recent data suggesting that crosstalk between SRC- 3FL (from the nucleus) and SRC-3 ?4 (at the plasma membrane) is critical for coordinate control of cell proliferation and motility, expansion of this concept will be a major focus of this renewal application. Finally, our preliminary data show that Gene Regulated by Estrogen in Breast -1 (GREB1 (previously known as an estrogen target)) plays a critical role in the determination of the ER- positive luminal epithelial cell type and in the response of the differentiated target cell to estrogen. Therefore, a major element of this proposal will be to determine how ER, SRC-3FL and GREB1 interact to maintain identity of the luminal epithelial cell during its normal proliferative response to estrogen and promote loss of differentiation during mammary tumorigenesis. PUBLIC HEALTH RELEVANCE: SRC-3 full length (SRC-3FL) and SRC-3 ?4 are controlled by complex posttranslational modifications that regulate their genomic and non-genomic functions in the mammary epithelium. Here, we describe new findings that demonstrate an important signaling relationship between the SRC-3 isoforms, the estrogen receptor (ER) and GREB1 (an estrogen receptor target gene) which are important for maintaining mammary epithelial cell identity and its responsiveness to hormone. This proposal is designed to elucidate how these proteins function together to control events in the cell nucleus and membrane to regulate the normal and pathological biology of distinct cell types in the mammary epithelium.